Ingenol-3-mebutate (trade-name: Picato®) has been disclosed as protein kinase C activator that can be used for the treatment of actinic keratosis (WO 2012/010172, incorporated herein by reference). Ingenol-3-angelate (Sayed, M. D. et.al.; Experienta, (1980), 36, 1206-1207, incorporated herein by reference) can be isolated from various Euphorbia species, and particularly from Euphorbia peplus (Hohmann, J. et. al; Planta Med., (2000), 66, 291-294, incorporated herein by reference) and Euphorbia drummondii by extraction followed by chromatography as described in U.S. Pat. No. 7,449,492, incorporated herein by reference.
Ingenol-3-mebutate is also known as ingenol-3-angelate, 2-methyl-2(Z)-butenoic acid (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H-2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6-yl ester; PEP005, ingenol mebutate, with an IUPAC name: (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-Dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H-2,8a-methanocyclopenta[a]cyclpropa[e][10]annulen-6-yl(2Z)-2-methylbut-2-enoate. The chemical formula for ingenol-3-mebutate is C25H34O6 having a molecular weight of 430.53 g/mol. The chemical structure of ingenol-3-mebutate is shown below, along with numbering of some atoms that are referred to herein.

WO 2012/010172 (incorporated herein by reference) discloses a process for preparation of ingenol-3-mebutate from ingenol (structure shown below) involving reacting one or both hydroxyl groups in positions 5 and 20 of ingenol with a suitable hydroxyl protecting agent, and where the hydroxyl protecting group are the same or different, to obtain an intermediate compound (hydroxyl protected ingenol). An esterification reaction is then carried out on the intermediate compound to esterify the hydroxyl group at the 3-position to form a hydroxyl protected ingenol-3-mebutate. Subsequently, the hydroxyl protecting groups are removed to obtain ingenol-3-mebutate.

WO 2014/012836 (incorporated herein by reference) discloses an alternate process for preparation of ingenol-3-mebutate from 20-deoxy-ingenol by selective angeloylation to 20-deoxy-ingenol-3-angelate, followed by oxidation to ingenol-3-angelate.
The processes disclosed in WO 2012/010172 and WO 2014/012836 are batch processes, which can require intermittent introduction of frequently changing raw materials, varying process conditions within the vessel, and different purification methods. Typically, in batch processing, vessels are often idle while waiting for raw materials or undergoing quality control checks and cleaning. In contrast, a continuous operation can allow a constant feed of raw materials to the process vessel and continual product withdrawal. Moreover, a continuous process can provide a number of benefits, while also generally being more economical than batch processes.
There is a need in the art for an alternate process for preparation of ingenol-3-mebutate. In addition, there is a need in the art for a process for regioselective preparation of ingenol-3-mebutate from ingenol. Further, there is a need in the art for a continuous process for preparation ingenol-3-mebutate.